Numerous derivatives of aroyl-substituted pyrroles have been prepared by Friedel-Crafts' reaction between an appropriate aroyl halide and a pyrrole-2-acetic acid derivative in the presence of a Lewis acid, preferably using a metallic halide catalyst such as aluminum chloride, see U.S. Pat. No. 3,752,826. Such compounds are useful as anti-inflammatory agents and as synthetic intermediates. However, the use of a metallic halide catalyst requires considerable efforts to purify the product and remove the metallic constituent from the reaction product, especially for therapeutic use of the product as an anti-inflammatory agent. According to the present invention, a process which does not employ metallic halides as a catalyst has now been discovered.
The present invention relates to the acylation of a pyrrole derivative, for example, a pyrrole-2-acetic acid derivative using a mixed anhydride. Classically, acid anhydrides have been prepared by reaction of an acid halide and a salt or by driving the equilibrium existing between a carboxylic acid and an acid anhydride to prepare the desired acid anhydride. Mixed anhydrides have been prepared by Karger and Mazur, J. Org. Chem., Vol. 36, No. 4, p. 528-540 (1971), which describes the synthesis of mixed sulfonic-carboxylic anhydrides, utilizing sulfonic acid and either acyl chloride or anhydride.
According to Karger and Mazur, supra, p. 529, it is possible to prepare mixed anhydrides by heating an excess of carboxylic anhydride with sulfonic acid for 20-30 minutes at 120.degree.C followed by removal under high vacuum of the excess anhydride together with the free acid formed according to the following equation: EQU (CH.sub.3 CO).sub.2 O + CH.sub.3 C.sub.6 H.sub.4 SO.sub.2 OH .fwdarw. CH.sub.3 COOSO.sub.2 C.sub.6 H.sub.4 CH.sub.3 + CH.sub.3 COOH
Accordingly, acetyl para-toluenesulfonate and trichloroacetyl para-toluenesulfonate were prepared. However, mixed anhydride preparation from higher molecular weight anhydrides and acids is complicated by involatility of both anhydride and acid. This, according to the authors necessitates higher temperatures causing decomposition of product. As a further aspect of the present invention, there is provided a process for preparation of mixed anhydrides from higher molecular weight anhydrides without the necessity for higher temperatures or distilling off the acid formed on reaction.